Abstract
iRhom proteins are catalytically inactive relatives of rhomboid intramembrane proteases. There is a rapidly growing body of evidence that these pseudoenzymes have a central function in regulating inflammatory and growth factor signalling and consequent roles in many diseases. iRhom pseudoproteases have evolved new domains from their proteolytic ancestors, which are integral to their modular regulation and functions. Although we cannot yet conclude the full extent of their molecular and cellular mechanisms, there is a clearly emerging theme that they regulate the stability and trafficking of other membrane proteins. In the best understood case, iRhoms act as regulatory cofactors of the ADAM17 protease, controlling its function of shedding cytokines and growth factors. It seems likely that as the involvement of iRhoms in human diseases is increasingly recognized, they will become the focus of pharmaceutical interest, and here we discuss what is known about their molecular mechanisms and relevance in known pathologies.
Highlights
Rhomboids are intramembrane serine proteases, first discovered in Drosophila, where they proteolytically release membrane-tethered EGF ligands, thereby activating signalling [1,2]
Rhomboids were found in a burst of discovery of several different families of intramembrane proteases which collectively introduced the radical idea of regulated proteolysis within membrane lipid bilayers [3]
Rhomboid-like proteins are localized in many cellular membranes and, despite large gaps in our knowledge of their function, a wide range of roles have already been uncovered, such as intercellular signalling, mitochondrial dynamics, parasite invasion and protein quality control [8,9]
Summary
Rhomboids are intramembrane serine proteases, first discovered in Drosophila, where they proteolytically release membrane-tethered EGF ligands, thereby activating signalling [1,2]. Beyond the conservation of rhomboid proteases, more extensive bioinformatic analyses identified a much wider rhomboid-like superfamily [5,6] comprising rhomboid proteases, as well as many relatives that contain residues that disrupt their active site, rendering them proteolytically inactive. Among these ‘pseudoproteases’, the iRhoms, the focus of this review, are the most closely related to the rhomboid proteases. Rhomboid-like proteins are localized in many cellular membranes and, despite large gaps in our knowledge of their function, a wide range of roles have already been uncovered, such as intercellular signalling, mitochondrial dynamics, parasite invasion and protein quality control [8,9]. License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited
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